Ornithine Transcarbamylase Deficiency Wiki
Welcome to the Ornithine Transcarbamoylase Deficiency Wiki Intro The Urea Cycle The urea cycle is a crucial metabolic pathway in the body as it is the principal means of excreting nitrogen in urea-producing organisms. This is especially important as the accumulation of ammonia is toxic in the body and has been linked to death as well as various complications, including central nervous system dysfunction and a comatose state. The urea cycle consists of six key enzymes: # Carbamoyl-phosphate synthetase I (CPS1) # Ornithine transcarbamylase (OTC) # Argininosuccinate synthetase (ASS1) # Argininosuccinate lyase (ASL) # Arginase 1 (ARG1) # N-acetylglutamate synthase (NAGS) The pathway begins in the mitochondria, with N-acetylglutamate being synthesized by NAGS using glutamate and acetyl CoA. N-acetylglutamate binds to CPS1, which induces a conformational change to reveal the enzyme's active site. CPS1 catalyzes the synthesis of carbamoyl phosphate by combining a bicarbonate group with an ammonia group that is formed as a result of protein metabolism. OTC is then able to combine the carbamoyl phosphate with ornithine in order to create citrulline. Citrulline is transported to the cytosol and is combined with asparate by ASS1 in order to make argininosuccinate. This product is then cleaved by ASL into fumarate and arginine. Finally ARG1 cleaves arginine to produce ornithine, which returns to the mitochondria via the mitochondrial ornithine transporter 1 protein for re-use in the urea cycle, as well as urea, which is excreted as waste. In all, this pathway provides the body a means of effectively excreting nitrogen waste, and thus, any disruptions in the urea cycle may result in critical circumstances. Symptoms and Implications of OTC Deficiency Josh + Adam Structure and Mechanism of the OTC Enzyme Human ornithine transcarbamoylase (EC 2.1.3.3) is a trimer with three identical subunits in its active form. Each subunit is 354 amino acids in length consisting of 14 alpha-helices, and 9 beta-sheets (Figure R1). Each subunit also has 2 domains, when the catalytic trimer is formed the CP binding domains are near the interior of the protein, and the ORN binding domains are exterior (Figure R2). The active site of OTC is made up of 22 amino acid residues which catalyses the reaction between carbamyl phosphate (CP) and ornithine (ORN) to form citrulline. The proposed mechanism for the catalytic actions of OTC involves a Sn2 displacement attack initiated by the amino group the the carbonyl carbon atom of the CP domain. Mutations in OTC are among the most common inborn errors of the urea cycle and cause a deficiency in its catalytic effects, leading to various clinical manifestations. Many of these mutation are near its active site and directly interfere with substrate binding (eg. K88N, R92Q, T93A). Other mutations could lead to a variety of effects such as disrupt protein folding/destabilize protein (eg. S192Q, G195R, Q216E), interfere with domain closure (eg. T178M, E181G), alter the charge of subunit surface to disrupt assembly of the trimer (eg. G79E, A102E, D126G), and interfere OTC’s interactions with other proteins or the membrane (eg. R40H, Q180H, F354C). The effects of these mutations will be explored more in-depth in the next section. OTC Mutations Adam + Mike (Adam's stuff) A study by McCullough et al. attempted to characterize the correlation between genotype (the genetic defects present) and phenotype (how the patient presents) in patients with OTC deficiency. The study examined 157 families, collected tissue samples from patients ranging from neonates to adults, and identified 89 mutations. The first key findings are displayed in Table 1 of the article. This table displays current understanding of phenotypic classifications of patients with OTC deficiency. Many mutations associated with neonatal-onset symptoms affect consensus splice site sequences. In contrast, late-onset phenotypes often have missense mutations that do not affect splice site sequences. Almost all heterozygous females who present with hyperammonemia have neonatal-onset genotypes. Interestingly, the age of OTC deficiency symptom presentation ranges from person to person. Newborns who lack full OTC activity will present with symptoms at birth, and the disease almost always causes mortality within the first few days of life. However, patients with residual OTC activity vary in their age of presentation, with the oldest detected being 62 years old. Table II of the articles presents further interesting information on the age of onset of various OTC mutations found in males. The age of presentation varies greatly in age; in some cases symptoms present as a child, and in other cases symptoms present as an adult. This strongly suggests that environmental factors, including amount of exercise and diet, may influence the onset of OTC deficiency symptoms in males presenting with a late-onset genotype. Of interest are the peak ammonia levels in males presented with either neonatal or late-onset hyperammonemia. The median plasma ammonia levels are extremely different between the two groups, further implying that patients with late-onset symptoms have OTC mutations that allow residual activity of the enzyme. Of particular interest is how males and females differ in their presentation of phenotypes. Figure 3 from the paper describes ammonia nitrogen incorporation into urea, and clearly identifies the differences between males and females. Of interest is how females presenting with symptoms were almost always heterozygotes with a neonatal-onset type mutation. These results indicate that females can often be asymptomatic, yet still carry a mutation that would confer late-onset symptoms in males. A similar study, conducted by Leibundgut et. al, reports on several mutations found in clinical cases of OTC deficiency. A mutation in arginine 141, which results in the introduction of a stop codon, is a recurrent mutation based on the literature. It has been linked to a neonatal onset of disease in males and is characterized by undetectable OTC activity. The patient reported on in the study died 1 month after birth. A H302Y mutant has been found to modify the structure of the ornithine binding site of OTC. Similarly, there was no OTC activity detected in the patient, who fell into a comatose state on the second day of life and subsequently passed away on the 6th day. The authors hypothesized that drastic effects came about as a result of the substitution of the basic histidine residue for the neutral tyrosine residue. The K88N and the P220A OTC mutants were shown to demonstrate partial residual OTC activity. The former patient had been healthy until the age of 4, but from then on, experienced episodic vomiting and lethargy. On the other hand, the latter patient suffered from protracted vomiting early on in life, fell into a comatose state at 2.5 years and eventually died as a result of cardiac insufficiency. Finally, the K343T mutation in OTC introduced an additional positive charge to the protein structure, which was suspected to affect folding. However, the patient was reported to demonstrate residual enzyme activity, and as a result, it was hypothesized that this region of the enzyme was robust to modifications. Similar to other patients, the patient suffering from this mutation demonstrated repeated episodes of lethargy, as well as elevated blood ammonia levels and undetectable citrulline levels. Despite the varying manifestations and outcomes of OTC deficiencies, clinical cases often demonstrate an elevation in orotic acid, a byproduct formed from carbamoyl phosphate as a result of an inability to metabolize carbamoyl phosphate through the urea cycle. OTCD Treatments Josh Authors Latest activity (delete this part) Photos and videos are a great way to add visuals to your wiki. Find videos about your topic by exploring Wikia's Video Library. __FORCETOC__ Category:Browse